Individuals with HIV infection on suppressive antiretroviral therapy continue to have elevated rates of cognitive impairment. Finding an objective, inexpensive biomarker for cognitive impairment in fluids such as plasma and cerebrospinal fluid (CSF) or neuroimaging would be useful to diagnose worsening impairment and follow with treatment. While there have been many markers suggested for increasing peripheral inflammation, this activation does not always correlate with impairment. Exosomes are spherical vesicles that encapsulate cellular proteins, mRNAs and miRNAs from the cytoplasm of the parent cell. Exosomes are shed into the extracellular space by cells under normal and pathological conditions. They are a form of cell-to-cell communication and their content often mimics the parent cell. We demonstrate that we can isolate plasma exosomes and capture by immunoadsorption, neuron-derived exosomes (NDE). We show that the total number of NDE from HIV-infected subjects is decreased compared to uninfected controls. We also show an increase in high mobility group box 1 (HMGB1) protein, an alarmin that signals cellular stress and damage, in all subjects with mild cognitive impairment, including several impaired subjects without HIV infection. We further demonstrate that the number of NDE have a significant positive correlation with increasing age in HIV+ subjects, unlike uninfected controls. We hypothesize that plasma NDE will have cargo that correlates with increasing cognitive impairment in HIV infection. We also posit that normal aging will influence the exosome cargo. We propose to characterize the exosome protein cargo using mass spectrometry and identify targets that parallel neuronal cell health in normal aging and increasing cognitive impairment in HIV-infection. This allows for a noninvasive, inexpensive technique to monitor brain health and response to therapy. !